Over 61 million Americans have some type of cardiovascular disease that is the leading cause of death in this country. Obesity and stress are two high risk factors for cardiovascular disease, especially hypertension. The melanocortins consist of a family of peptides derived from the common precursor pro-opiomelanocortin. These peptides include alpha-, beta-, and gamma-melanocyte stimulating and adrenocorticotropic hormones. Melanocortins have been implicated in feeding behavior, obesity and stress responses. For example, disruption of melanocortin containing neurons produces over eating and obesity. Mild stress has been reported to elicit over eating that can lead to obesity. In addition, melanocortin levels are elevated in stressful situations. These observations suggest that there may be a link between melanocortins, obesity, stress and cardiovascular disease. A prerequisite for understanding the role of melanocortins in cardiovascular function during obesity and stress is a clear understanding of the role of these peptides in the central cardiovascular regulation in normal conditions. The goal of the present project is to investigate the mechanism of cardiovascular actions of melanocortins in the nucleus tractus solitarius, caudal ventrolateral medullary depressor area, rostral ventrolateral medullary pressor area, the nucleus ambiguus, and the intermediolateral cell column of the thoraco-lumbar cord. These areas of the central nervous system are known to be involved in the regulation of cardiovascular function. Dense neuronal networks containing melanocortins have been identified in these regions. The hypothesis central to this project is that melanocortins excite neurons located in the medullo-spinal regions involved in cardiovascular regulation. The hypothesis is based on our preliminary results and published reports in which electrophysiological studies have shown excitation of neurons in specific regions of the brain. In each of the abovementioned regions, pharmacological and electrophysiological techniques will be used to investigate the mechanism of action of melanocortins. The information generated from this project will eventually be helpful in understanding the mechanisms connecting melanocortins, obesity, stress and cardiovascular disease. Furthermore, this information will help in developing novel and rational regimens of treatment for cardiovascular disease.